■CART疗法在复发性FL患者的治疗中产生了范式转变。在这些治疗后优化疾病监测的策略越来越必要。这项研究探索了具有个性化可追踪突变的创新签名的ctDNA监测的潜在价值。
■11例接受抗CD19CAR-T细胞治疗的FL患者被包括在内。一个人没有回应,被排除在外。在开始淋巴耗尽化疗之前进行基因组分析以鉴定适于LiqBio-MRD监测的体细胞突变。在59个cfDNA随访样品上进一步分析基线突变的动力学(每个患者4.5个)。PET/CT检查在第+90、+180、+365天进行,每6个月进行一次,直至疾病进展或死亡。
■经过36个月的中位随访,所有患者均以CR为最佳反应。两名患者进展。最常见的突变基因是CREBBP,KMT2D和EP300。ctDNA和PET/CT的同时分析可用于18个时间点。当PET/CT阳性时,4份ctDNA样本中有2份为LiqBio-MRD阴性.这两个阴性样品在两次评估中对应于具有独特肠系膜肿块的女性,从未复发。同时,根据我们的LiqBio-MRD分析(100%),14个PET/CT阴性图像无突变。到第+7天,没有患者的LiqBio-MRD测试为阴性。有趣的是,所有持续有反应的患者在输注后3个月或3个月左右均未检测到ctDNA.两名患者的PET/CT和ctDNA水平显示结果不一致。在这些病例中没有证实进展。所有进展患者进展前均为LiqBio-MRD阳性。
■这是使用ctDNA监测FL对CAR-T细胞治疗反应的原理证明。我们的结果证实,非侵入性液体活检MRD分析可能与反应相关,可用于监测反应。ctDNA分子反应的协调定义和准确确定评估ctDNA反应的最佳时机对于这种设置是必要的。如果使用ctDNA分析,我们建议将CR患者的PET/CT随访限制为临床怀疑复发,以避免假阳性结果。
CART therapy has produced a paradigm shift in the treatment of relapsing FL patients. Strategies to optimize disease surveillance after these therapies are increasingly necessary. This study explores the potential value of ctDNA monitoring with an innovative signature of personalized trackable mutations.
Eleven FL patients treated with anti-CD19 CAR T-cell therapy were included. One did not respond and was excluded. Genomic profiling was performed before starting lymphodepleting chemotherapy to identify somatic mutations suitable for LiqBio-MRD monitoring. The dynamics of the baseline mutations (4.5 per patient) were further analyzed on 59 cfDNA follow-up samples. PET/CT examinations were performed on days +90, +180, +365, and every six months until disease progression or death.
After a median follow-up of 36 months, all patients achieved a CR as the best response. Two patients progressed. The most frequently mutated genes were CREBBP, KMT2D and EP300. Simultaneous analysis of ctDNA and PET/CT was available for 18 time-points. When PET/CT was positive, two out of four ctDNA samples were LiqBio-MRD negative. These two negative samples corresponded to women with a unique mesenteric mass in two evaluations and never relapsed. Meanwhile, 14 PET/CT negative images were mutation-free based on our LiqBio-MRD analysis (100%). None of the patients had a negative LiqBio-MRD test by day +7. Interestingly, all durably responding patients had undetectable ctDNA at or around three months after infusion. Two patients presented discordant results by PET/CT and ctDNA levels. No progression was confirmed in these cases. All the progressing patients were LiqBio-MRD positive before progression.
This is a proof-of-principle for using ctDNA to monitor response to CAR T-cell therapy in FL. Our results confirm that a non-invasive liquid biopsy MRD analysis may correlate with response and could be used to monitor response. Harmonized definitions of ctDNA molecular response and pinpointing the optimal timing for assessing ctDNA responses are necessary for this setting. If using ctDNA analysis, we suggest restricting follow-up PET/CT in CR patients to a clinical suspicion of relapse, to avoid false-positive results.